Sage May Be Forced To Simplify Brexanolone Dosing Regimen
Executive Summary
Advisory committee members warned of dosing errors and other potential problems with the titration/taper regimen used in the clinical trials, arguing a simpler dosing schedule also could increase patient access.
SAGE Therapeutics Inc. may be forced to simplify the dosing regimen for its proposed postpartum depression treatment brexanolone in order to get approval in the US after advisory committee members warned that administration may prove difficult for trained hospital staff.
Such a change might be requested as part of a postmarketing commitment, and while sponsors tend to find such obligations burdensome, developing a new dosing scheme could actually help the product commercially.
Brexanolone, proposed trade name Zulresso, would become the first treatment to receive a postpartum depression indication if approved. The product could help reduce symptoms in less than three days, as opposed to other antidepressants, which may take weeks to show improvement.
However, the product, a purported positive allosteric modulator of GABAA receptors, requires a complicated 60-hour infusion with multiple bag changes, titrations and tapers. In addition, there are questions about the maximum dose to use in the regimen. (See sidebar.)
Members of the joint-Psychopharmacologic Drugs and Drug Safety and Risk Management advisory committee, which enthusiastically endorsed the product Nov. 2, said that even use in a controlled setting with constant patient monitoring, which FDA wants, may not belay fears of medication errors.
Gregory Burger, medication safety coordinator at Stormont-Vail HealthCare in Topeka, Kan., said the required four bag changes during the infusion will be difficult for hospital staff to handle. He and others suggested human factors studies to find the simplest and safest administration system.
Burger also indicated that the necessary titrations and tapers may come at unusual times, which also may create problems.
"This four-bag thing is a total nonsense and it's going to cause craziness and med error after med error," Burger said.
During the infusion period, new bags are required at hours 12, 24, 36 and 48. The 90 mcg/kg per hour dose requires titrations up at hour four and hour 24, followed by tapers at hour 52 and hour 56. An alternative 60 mcg/kg per hour regimen would maintain the dose at hour 24 and hold the tapering until hour 56, according to FDA briefing documents. (See graph of the dosing schedule adapted from the documents.)
To further complicate matters, Sage proposed multiple brexanolone concentrations based on weight, although committee members, FDA and the company agreed that brexanolone bags had to be distributed in one concentration.
FDA Says Use In Controlled Setting Allows Time to Simplify Dosing
Committee members tried to find potential options for a simpler infusion schedule during the meeting. Anne-Michelle Ruha, director of the medical toxicology fellowship program at Banner University Medical Center in Arizona, asked whether the taper was necessary given there were no withdrawal symptoms seen in clinical trials. She said the multiple dose changes likely will lead to errors.
Tiffany Farchione, deputy director of the Division of Psychiatry Products, said the agency also is worried about potential adverse events if the dose is not tapered by mistake or the patient stops the infusion early.
"It is a little bit of a conundrum because we don't have data with other more simplified dosing regimens to look at," she said. "If this were to be approved in its current iteration, we would probably ask for data to say can you look at this in some other way to see if we still see efficacy with a different dosing regimen that might be easier, less prone to potential error, etc."
DPP Director Mitchell Mathis said the agency is discussing a simpler system with Sage. Mathis also said the agency thought if it was used in controlled settings with skilled staff, Sage would be able research a simpler regimen, potentially post-approval.
Mathis also said while there may be easier dosing regimens for brexanolone, "we just haven't laid those out yet or thought about those to the point of asking the sponsor to do them."
"When we reached the point in our discussion of this where we agreed if this was to happen it would happen in a controlled environment, I think we all decided we had time to sort this out," he said.
Committee members recommended brexanolone be administered in a hospital or other certified health care setting, in part to protect patients and their babies from injury. FDA found the potential for patients to lose consciousness or experience dizziness during the infusion and said they should be monitored throughout. (Also see "Sage's Brexanolone Could Be Transformative, But Only In Controlled Settings, US FDA Panel Says" - Pink Sheet, 2 Nov, 2018.)
More Access, More Errors?
Committee members also were worried that attempts to increase access to the medication could create more opportunities for errors and injuries.
The agency did not want to limit administration to only inpatient hospitals, but advisory committee members were concerned how non-acute care settings, such as skilled nursing facilities, would obtain brexanolone and ensure the product is properly prepared.
Cynthia LaCivita, director of the Division of Risk Management in FDA's Office of Medication Error Prevention and Risk Management, told the committee those details had not been decided yet.
She said the proposed Risk Evaluation and Mitigation Strategy for the product, which would include Elements to Assure Safe Use, is expected to describe the proper certified settings for administration, dose preparation and storage.
"Preparing the bags is fairly complicated too because it's based on weight and they're adjusting the volumes," she said. "I would think that it would have to be done at a pharmacy."
Committee Chair Rajesh Narendran, attending psychiatrist at the Western (Pa.) Psychiatric Institute and Clinics, also suggested that a simpler and more patient-friendly regimen, such as an interrupted infusion given for a few hours over several days, could increase patient access.
"Is there any other way mechanistically to alter the protocol where it can be administered to make it more accessible?" he asked.
Sage and FDA agreed that home infusions would not be allowed upon approval, but indicated they eventually may be allowed if safety could be assured. FDA and committee members raised several concerns about patient monitoring in a home setting. (Also see "Sage's Postpartum Depression Drug Brexanolone Faces Loss-Of-Consciousness Questions" - Pink Sheet, 31 Oct, 2018.)